- Email: [email protected]
Management recommendations for invasive dental treatment in patients using oral antithrombotic medication, including novel oral anticoagulants
Vol. 116 No. 6 December 2013
Management recommendations for invasive dental treatment in patients using oral antithrombotic medication, including novel oral anticoagulants Denise E. van Diermen, MD, PhD,a Isaäc van der Waal, DDS, PhD,b and Johan Hoogstraten, PhDc Academic Centre for Dentistry Amsterdam, Amsterdam, the Netherlands
Objective. The aims were (1) to search the scientific literature from 2007 to 2012 for guidelines and new studies on the dental management of patients using oral antithrombotic medication; (2) to summarize the articles’ evidence and recommendations; and (3) to propose an updated clinical practice guideline for general dentists. Study Design. A systematic literature search in MEDLINE, Embase, and the Guideline websites, from October 2007 to October 2012, produced articles that were critically evaluated. Results. The systematic literature search for guidelines yielded 74 citations (MEDLINE, 45; Embase, 22; and the Guideline websites, 7). Of these, only 2 guideline publications and 2 systematic reviews met the inclusion criteria. They yielded 32 recommendations. Conclusions. The evidence and subsequent recommendations from published guidelines all point in the same direction: do not interrupt oral antithrombotic medication, not even dual antiplatelet therapy, in simple dental procedures. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:709-716)
Oral antithrombotic medication (OAM) has long been used successfully to treat a variety of thrombotic diseases, such as myocardial infarction, stroke, and deep venous thrombosis, and to prevent cardiovascular diseases.1-4 For decades, doctors and patients have worried about the adverse side effects of these medicines, mainly consisting of bleeding complications, either spontaneously or perioperatively. Also in dentistry, this has been a major concern for years, resulting in the advice to temporarily discontinue OAM before invasive dental treatments, such as dental extractions.5-7 Since 1998, several publications have appeared in medical and dental journals5,6,8-12 suggesting that bleeding complications after dental procedures in patients who did not discontinue their antithrombotic medication might not be as serious as previously thought. Furthermore, several studies were published suggesting that the risk of thrombosis after discontinuing OAM might outweigh the bleeding risks while continuing OAM. These considerations have led to several clinical practice guidelines (CPGs) on this topic.13-16 In 2009, a systematic search for guidelines and critical evaluation of these guidelines was performed, a
Assistant Professor and Director of Medicine, Clinic for MedicalDental Interaction, Academic Centre for Dentistry Amsterdam (ACTA). b Professor, Department of Oral and Maxillofacial Surgery/Oral Pathology, Vrije Universiteit Medical Center and Academic Centre for Dentistry Amsterdam (ACTA). c Professor, Department of Social Dentistry and Behavioural Sciences, Academic Centre for Dentistry Amsterdam (ACTA). Received for publication Apr 24, 2013; returned for revision Jul 18, 2013; accepted for publication Jul 23, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.07.026
which led to the conclusion that with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument, only 2 guidelines met the criteria of “good” CPGs.17 One was developed in the United Kingdom18 and one at the International World Workshop of the American Academy of Oral Medicine.19 The aim of this study was to review the dental literature from 2007 to 2012 for additional publications and to propose a CPG for general dentists reflecting the latest evidence as of 2013.
METHODS We used the search strategies from our previous systematic search for guidelines on invasive dental treatment in patients using OAM (as described and published in 200917) to obtain additional guidelines, systematic reviews, and randomized controlled trials (RCTs) published between October 2007 and October 2012 (Tables I and II). We searched MEDLINE, Embase, and the Guideline websites (the National Guideline Clearinghouse [www.guidelines.gov], the Scottish Intercollegiate Guidelines Network [www.sign. ac.uk], the Canadian Medical Association Infobase for Clinical Practice Guidelines [http://www.cma.ca/cpgs/],
Statement of Clinical Relevance General dentists can use the evidence-based recommendations derived from the available evidence described in this article for management of patients using oral antithrombotic medication, including the novel oral anticoagulants. 709
ORAL MEDICINE 710 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table I. MEDLINE search strategy (October 28, 2012) Query No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
Query terms
No. of results
guideline* or practice guideline recommendation* standard* of care practice standard* OR professional standard algorithm OR clinical algorithm* practice algorithm clinical guideline* expert* consensus 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 anticoagulant* aspirin coumadin coumarin* warfarin clopidogrel oral anticoagulant* ticlopidine 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 dentistry dental treatment* dental surgery dental extraction* dental scaling dentoalveolar procedure* dental implant* 19 or 20 or 21 or 22 or 23 or 24 9 and 18 and 25 and 26 limit 27 to human limit 28 to English OR Dutch language limit to date October 2007eOctober 2012
241.975 129.340 244.041 1675 206.863 10.184 5.833 8.286 743.740 193.641 50.447 19.098 14.480 18.744 7.666 4.638 7.293 246.917 411.475 5.540 65.562 1.324 3.906 12 23.947 428.805 158 145 129 45
*The asterisk is a wildcard character.
the Guidelines International Network [www.g-i-n.net], Evidence-Based Medicine Guidelines [www.ebmguidelines.com], the National Institute for Clinical Excellence [www.nice.org.uk]). Inclusion/exclusion criteria Guidelines were included if they were developed for the dental management of patients using antiplatelet or oral anticoagulation medication on the basis of consensus or evidence-based methods. If the guidelines had been updated, the latest version was included. Guidelines based on commentaries and narrative reviews were excluded. Only guidelines written in English or Dutch were reviewed. Systematic reviews and meta-analyses were included if (1) the patients were either on antiplatelet therapy or on vitamin K antagonists (VKAs); (2) the patients had invasive dental procedures performed; (3) the patients were analyzed for bleeding and thrombosis outcomes; and (4) the reviews and metaanalyses included RCTs or cohort studies of sufficient scientific quality. To evaluate the study quality, we used standardized evaluation forms published on the website of the Dutch Cochrane Center (www.dcc.cochrane.org).
RESULTS The systematic literature search for guidelines from October 2007 to October 2012 yielded 74 citations (MEDLINE, 45; Embase, 22; and the Guideline websites, 7) (see Tables I and II). Of these, only 2 guideline publications met the inclusion criteria.20,21 Furthermore, one systematic review and meta-analysis was published in 2009 on dental procedures in patients using warfarin, which reviewed all studies that appeared until June 2008.22 Napenas et al.23 performed a systematic review on dental procedures in patients using single or dual antiplatelet therapy, which included all studies published through September 2011. We collected the levels of evidence (Table III) and levels of recommendations (Table IV) as described and provided by the authors.20,21 In Tables III and IV, we added the results from our former study,17 in which 2 international guidelines were found to be AGREE-able, that is, compatible with the AGREE instrument’s methodologic recommendations.18,19 The recommendations and underlying levels of evidence that were extracted from these guidelines, systematic reviews, and one RCT are summarized in Table V. The gathered recommendations were formulated into a CPG proposal (Table VI). DISCUSSION AND CONCLUSIONS Since the publication in 2007 of 2 evidence-based guidelines in the United Kingdom and the United States,18,19 some additional evidence has emerged from 2 guideline publications, one systematic review on antiplatelet therapy and dental procedures,23 and one meta-analysis on procedures in patients using VKAs.22 Both systematic reviews conclude in concordance with the earlier published guidelines, stating that “continuing the regular dose of warfarin therapy does not seem to confer an increased risk of bleeding when compared with discontinuing or modifying warfarin dose in patients undergoing minor dental procedures”22 and “that there is no indication to alter or discontinue antiplatelet therapy before invasive dental procedures.”23 Several considerations still have to be taken into account. For example, most studies that were included in the systematic reviews were performed in hospital settings and not in outpatient settings. Neither were they performed in patients with comorbid conditions that might influence bleeding after invasive dental procedures. Several medications are known to influence the coagulation system, including nonsteroidal antiinflammatory drugs and drugs that have a potentiating interaction with VKAs, including antifungal agents such as miconazole, which can increase international normalized ratio (INR) values and might enhance
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 711
Table II. Embase search strategy (October 28, 2012) Query No.
Query terms
# 25 #24 AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim #24 #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 #23 dental AND implant* AND [2005-2012]/py #22 dentoalveolar AND procedure* AND [2005-2012]/py #21 dental AND scaling AND [2005-2012]/py #20 dental AND extraction* AND [2005-2012]/py #19 dental AND (‘surgery’/exp OR surgery) AND [2005-2012]/py #18 dental AND treatment* AND [2005-2012]/py #17 ‘dentistry’/exp OR dentistry AND [2005-2012]/py #16 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 #15 ‘ticlopidine’/exp OR ticlopidine AND [2005-2012]/py #14 ‘oral’/exp OR oral AND anticoagulant* AND [2005-2012]/py #13 ‘clopidogrel’/exp OR clopidogrel AND [2005-2012]/py #12 ‘warfarin’/exp OR warfarin AND [2005-2012]/py #11 coumarin* AND [2005-2012]/py #10 ‘coumadin’/exp OR coumadin AND [2005-2012]/py #9 ‘aspirin’/exp OR aspirin AND [2005-2012]/py #8 anticoagulant* AND [2005-2012]/py #7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 #6 algorithm OR clinical AND algorithm* AND [2005-2012]/py #5 practice AND standard* OR professional AND (‘standard’/exp OR standard) AND [2005-2012]/py #4 practice AND standard* OR professional AND (‘standard’/exp OR standard) AND [2005-2012]/py #3 standard* AND of AND care AND [2005-2012]/py #2 recommendation* AND [2005-2012]/py #1 guideline* OR practice AND guideline AND [2005-2012]/py
No. of results 44 219,781 41,566 604 1,353 12,210 91,736 76,612 123,752 195,707 5,458 40,826 25,821 29,769 39,104 28,953 65,524 186,803 637,170 39,686 218,811 218,811 412,918 89,971 161,358
*The asterisk is a wildcard character.
bleeding. Furthermore, local factors, such as the degree of inflammation of oral mucosa, might play a role in the risks of developing bleeding after dental surgical procedures. More studies are needed to investigate these additional factors. The preparation of CPGs has received a lot of scientific attention in recent years. Lately, the Board on Health Care Services from the Institute of Medicine in the United States published the latest opinions on good CPG making.24 The common opinion is that guidelines need to be conceived in a formal and transparent way, taking into account factors such as the quality of the guidelines as measured by the AGREE instrument (scope and purpose of the guideline, stakeholder involvement, rigor of development, clarity and presentation, editorial independence). Much attention has been given to the fact that certain evidence can lead to different recommendations, depending on the composition of the guideline committee. One example is the differences in recommendations in the guidelines for the prevention of bacterial endocarditis from the United Kingdom and the United States. In 2008, the UK National Institute for Health and Care Excellence (NICE)25 and the American College of Chest Physicians26 each made a guideline; the American guideline advises to prescribe antibiotics in certain groups of patients undergoing
invasive dental treatments, whereas the UK guideline advises against all antibiotic prophylaxis to prevent bacterial endocarditis in dental patients. Such differences gave rise to the development of the GRADE method (Grading of Recommendations Assessment, Development and Evaluation).27,28 Using the GRADE method can help in gaining insight into the guideline process and into the way recommendations are derived from evidence or even lack of evidence. In the present article, we have summarized only the recommendations based on evidence and used these to formulate a proposal for a CPG. In a definitive CPG, the independence of the guideline makers should be clearly stated, and GRADE should be used to clarify how evidence led to the recommendations. GRADE is one method that tries to tackle this problem and helps guideline makers to get insight into the underlying considerations and make them more explicit when making recommendations, by including the quality of the evidence and the strength of the recommendations. This method has been adopted by well-established guideline-making institutions, such as NICE, the World Health Organization, the Cochrane Collaboration, and the Dutch Institute for Healthcare Improvement (CBO) in the Netherlands.29 Another important issue is the opinion of the patients. The patients’ views
ORAL MEDICINE 712 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table III. Definition of the levels of evidence as described by other clinical practice guidelines Levels of evidence used by Aframian et al.19: Level A: Based on multiple randomized controlled trials Level B: Based on data from a single randomized trial or nonrandomized studies Level C: Expert opinion Classification of evidence levels used by Perry et al.18: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasiexperimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies, and case studies IV Evidence obtained from expert committee reports or opinions or from clinical experiences of respected authorities Levels of evidence of the Brazilian Society of Cardiology21 A. Evidence in several populations from multiple randomized clinical trials or meta-analyses B. Evidence in a limited group of populations from a single randomized clinical trial or from nonrandomized clinical studies C. Evidence in a very limited group of populations from consensus and experts’ opinions, case reports, and series Classification of evidence levels used by Douketis et al.20 Grade of recommendation
Benefit vs risk and burden
Methodologic strength of the supporting evidence
Strong recommendation, highquality evidence (1A)
Benefits clearly outweigh risk and burdens or vice versa.
Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies.
Strong recommendation, moderate-quality evidence (1B)
Benefits clearly outweigh risk and burdens or vice versa.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies.
Strong recommendation, low- or very-low-quality evidence (1C)
Benefits clearly outweigh risk and burdens or vice versa.
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Weak recommendation, highquality evidence (2A)
Benefits closely balanced with risks and burdens.
Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies.
Weak recommendation, moderatequality evidence (2B)
Benefits closely balanced with risks and burdens.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies.
Weak recommendation, low- or very-low-quality evidence (2C)
Uncertainty in the estimates of benefits, risks, and burdens; benefits, risk, and burdens may be closely balanced
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Implications Recommendation can apply to most patients in most circumstances. Further research is very unlikely to change our confidence in the estimate of effect. Recommendation can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate. Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate. The best action may differ depending on circumstances or patient or societal values. Further research is very unlikely to change our confidence in the estimate of effect. Best action may differ depending on circumstances or patient or societal values. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate. Other alternatives may be equally reasonable. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate.
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 713
Table IV. Definition of the grades of recommendations Classes of recommendations used by Aframian et al.19: Class I: Benefit to patients clearly outweighs any risks; procedure SHOULD be performed Class II: Conflicting evidence or a divergence of opinion about the usefulness of a procedure or treatment IIa: Benefit seems to outweigh the risk; weight of evidence is in favor of usefulness. IT IS REASONABLE to perform the procedure IIb: Benefit seems to outweigh the risk; usefulness is less well established. IT IS NOT UNREASONABLE to perform the procedure Class III: Risk outweighs the benefit; IT MAY BE HARMFUL AND IS UNHELPFUL. Procedure should NOT be performed Classification of grades of recommendations used by Perry et al.18: A. Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendation. (Evidence levels Ia, Ib) B. Requires the availability of well conducted clinical studies but no randomized clinical trials on the topic of recommendation. (Evidence levels IIa, IIb, III) C. Requires evidence obtained from expert committee reports or opinions or from clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV) Classification of degree of recommendations used by Brazilian Society of Cardiology21: Degree of Recommendation IdBenefit >>> Risk; the treatment/procedure must be indicated/administered; Degree of Recommendation IIadBenefit >> Risk; the choice for the treatment/procedure may help the patient; Degree of Recommendation IIbdBenefit > Risk; it is not defined if the treatment/procedure can help the patient; Degree of Recommendation IIIdRisk > Benefit; the treatment/procedure must not be performed because it does not help and may be harmful for the patient. Classification of grades of recommendation used by Douketis et al.20: 1A. Strong recommendation, high-quality evidence 1B. Strong recommendation, moderate-quality evidence 1C. Strong recommendation, low- or very-low-quality evidence 2A. Weak recommendation, high-quality evidence 2B. Weak recommendation, moderate-quality evidence 2C. Weak recommendation, low- or very-low-quality evidence
should be incorporated into the CPG-making process, because their perspectives warrant representation in the CPG. Two surveys relevant to the present study have been undertaken in the Netherlands, one among general dentists30 and one among oral and maxillofacial surgeons (OMSs)31; both found that dentists and OMSs have very variable management strategies in patients using antiplatelet medicines, such as aspirin, as well as in patients using VKAs, such as acenocoumarol. Both dentists and OMSs did express the need for a Dutch CPG on this topic. The accumulated evidence and recommendations from this study can be helpful to compose such a guideline. Unfortunately, international guidelines cannot be accepted unchanged, but have to be adapted to local circumstances and the needs of patients, dentists, and medical specialists. In the final version of a CPG, clinical questions for which no clinical studies have been undertaken are relevant. For example: Is it safe to treat patients with oral anticoagulation with dental implants, which dental procedures are considered more invasive, and what should be the management? How should dentists treat patients using the new generation of oral antithrombotic medicines, the novel oral anticoagulants (NOACs), such as rivaroxaban (Xarelto; Bayer Healthcare AG, Leverkusen, Germany) and dabigatran (Pradaxa; Boehringer Ingelheim, Ridgefield, CT)?
Turpie et al.32 advise not to interrupt rivaroxaban in procedures with a low risk of bleeding, such as simple tooth extraction. They also advise to avoid interventions at peak rivaroxaban activity, that is, 2 to 4 hours after dosing. Although there is no antidote to the NOACs, these medications have a short half-life of 5 to 9 hours, and their anticoagulating effect will wear off much sooner than that of VKAs, although the effect can last longer in elderly patients.32 In this journal, 2 comprehensive articles by Firriolo et al.33 and Little34 were published in 2012 about the NOACs and the suggested recommendations for dental procedures. Furthermore, the problem of implementing evidence and evidence-based CPGs into practice remains a problem. Several studies have found that since 2007, general dentists and OMSs throughout the Western world still advise patients to interrupt their OAM for simple dental treatments, exposing these patients to increased thrombotic risks.35 In this article we presented the scientific evidence and subsequent recommendations from the medical and dental literature until October 2012 that can be used as a sound base for an up-to-date CPG on the management of dental patients using OAMs and undergoing simple dental procedures. We excluded recommendations without scientifically evident sources and produced a management advice sheet for general dentists (see Table VI).
ORAL MEDICINE 714 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table V. Review of the recommendations from guidelines and systematic reviews on patients undergoing dental surgery using oral antithrombotic drugs (aspirin, clopidogrel, warfarin, and novel oral anticoagulants, such as dabigatran and rivaroxaban) Level of evidence* 1. Continuation of antithrombotic drugs a. Antiplatelet medications Do not interrupt low-dose aspirin therapy (100 mg or less) for outpatient dental procedures.19,21 Continue ASA around the time of minor dental procedures in patients who are receiving ASA for the secondary prevention of cardiovascular disease.20 Do not alter or stop single or dual antiplatelet therapy for invasive dental treatment (single or multiple tooth extractions, deep scaling and probing, biopsies, flap surgery, gingivectomy, alveoloplasty).19 b. Oral anticoagulants (warfarin) Oral anticoagulants should not be discontinued in the majority of patients requiring outpatient dental surgery, including extraction.18 When the INR is less than 3.5, do not modify or discontinue warfarin therapy for simple single dental extractions.19 When the INR is 3.5 or more and complicated or invasive oral surgery procedures are planned, discuss with physician.19 Continue VKAs with an oral prohemostatic agent in patients who require a minor dental procedure.20 Do not discontinue OAM before simple surgeries (e.g., extraction of 3 teeth, gingival surgery, periodontal scaling) in patients with INR < 3.0.21 Do not discontinue or modify the regular dose of warfarin for patients undergoing minor dental procedures (up to 5 dental extractions or 6 dental implants).21 c. Low-molecular-weight heparin Consult physician of patient on low-molecular-weight heparin for advice on continuing, altering, or stopping of medication before dental procedure.19 2. Antibiotics No need to change anticoagulation regimen when a single dose of prophylactic antibiotic is used.18,21 3. Preoperative measures Check INR 72 hours before dental surgery in patients that have stablez INRs.18 Check INR at least 24 hours before the dental procedure.21 Evaluation of INR 72 hours before the procedure is acceptable in stablez patients.21 Discuss with physician in charge when INR 3.0 and the planned procedures are more extensive.21 Assess the patient’s complete medical history.21 Schedule a larger number of visits when there is extraction of more than 3 teeth.21 Plan the surgeries earlier in the day and in the beginning of the week.21 4. Operative measures Inform the patients that minor bleeding or oozing from gingival mucosa may be more common when not interrupting VKAs during dental procedures.20 Minimize surgical trauma.21 Reduce areas of periodontal surgery and scaling and root planing (per quadrant).21 5. Postoperative pain control Do not prescribe NSAIDs and COX-2 inhibitors as analgesics.18 Consider using gelatin sponges, fibrin glue, fibrin adhesive dressing, oxidized cellulose, or 3-aminocaproic acid mouthwash.19 Give patients on OAC a 2-day regimen of postoperative 4.8% tranexamic acid mouthwash.19 Give patients who do not interrupt VKAs a 5-mL oral dose of tranexamic acid, 5 to 10 min before the dental procedure and 3 to 4 times daily for 1 to 2 days after the procedure.20 Remove nonabsorbable sutures after 4 to 7 days.21 Compress with gauze for 15 to 30 minutes after the surgical procedure.20 Use coagulating agents, such as gelatin sponges, oxidized regenerated cellulose, synthetic collagen, or tranexamic acid mouthwash in 4.8% aqueous solution during and 7 days after the surgery, using 10 mL, 4 times a day for 2 minutes.21 6. Referral Refer patients whose INR is unstable.z,18
Recommendation class, grade, or degreey
Level B
Class I Grade 2C
Level 1A
Class I
Level Ib
Grade A
Level A
Class I
Level A
Class I Grade 2C
Level C Level 1A
Class I
Level C
Level IV18/ Level C21
Grade C18/ Degree I21
Level Level Level Level Level Level Level
Grade A Degree I Degree I Degree I Degree I Degree I Degree I
Ib IC C C C C C
Grade 2C Level C Level C
Degree I Degree I
Level III Level B
Grade B Class I
Level A
Class I Grade 2C
Level C Level C Level C
Degree I Degree I Degree I
Level Ib
Grade A
OAC, oral anticoagulation; OAM, oral antithrombotic medication; TAR, thrombocyte aggregation inhibitor; ASA, acetylsalicylic acid; VKA, vitamin K antagonist; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase-2. *Levels of evidence are explained in Table III. y Degrees of recommendation are explained in Table IV. z No definition of stable and unstable INRs was given in the cited articles.
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 715
Table VI. Proposal for a 2013 clinical practice guideline for general dental practitioners Recommendations to general dental practitioners when planning invasive dental treatment for patients using oral antithrombotic medication and undergoing simple dental treatment (e.g., single or multiple dental extractions up to 3 teeth, up to 3 dental implants, scaling and root planing, probing, flap surgery, apex resection, alveoloplasty): 1. Continuation of OAM a. Do not interrupt single or dual TAR (such as ASA, clopidogrel, and carbasalate calcium). b. Do not interrupt VKAs if the INR is less than 3.5. c. Do not interrupt NOACs (direct thrombin inhibitors or Xa-inhibitors, such as apixaban, dabigatran, and rivaroxaban). Note: The anticoagulation regime does not require alteration when single-dose antibiotics for prophylaxis are provided; miconazole is contraindicated when VKAs or NOACs are taken. 2. Preoperative measures: a. Inform the patients that minor bleeding or oozing from gingival mucosa may be more common when not interrupting OAM during dental procedures. b. Check INR in patients using VKA at least 24 to 72 hours before the dental procedure; refer patients whose INR is higher than 3.5 to the hospital for evaluation and treatment. c. Advise patients on NOACs not to take medication 1 to 3 hours immediately before dental treatment. d. Assess the patients’ complete medical history and discuss with the physician in charge if renal or liver disorders are suspected or known; when INR 3.5 or the planned procedures are more extensive. e. Schedule extraction of more than 3 teeth over a larger number of visits (i.e., divide the load) and plan the surgeries earlier in the day and at the beginning of the week. 3. Perioperative measures: a. Minimize surgical trauma and reduce areas of periodontal surgery and scaling and root planing (per quadrant). b. Aim at primary closure of surgical wounds, including extraction wounds, using absorbable sutures. 4. Postoperative measures: a. Compress with gauze for 15 to 30 minutes after the surgical procedure; use coagulating agents, such as gelatin sponges, oxidized regenerated cellulose, synthetic collagen, or tranexamic acid mouthwash in 4.8% aqueous solution, during 1 to 2 days after the surgery, using 10 mL, 4 times a day for 2 minutes. b. Remove nonabsorbable sutures, if used, after 4 to 7 days. c. Do not prescribe NSAIDs and COX-2 inhibitors as analgesics to any patient on any antithrombotic medications. d. Provide the patients with oral and written instructions about the expected postoperative course and the measures they can take if bleeding occurs. OAM, oral antithrombotic medication; TAR, thrombocyte aggregation inhibitor; ASA, acetylsalicylic acid; VKA, vitamin K antagonist; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase-2.
The evidence and subsequent recommendations all point in the same direction: do not interrupt OAM, not even dual antiplatelet therapy, in simple dental procedures. With certain precautions, this seems to be a safe way to treat dental patients in need of minor invasive dental treatments while continuing their OAM.
REFERENCES 1. Seshasai SRK, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172:209216. 2. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;42: 227-276. 3. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative metaanalysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. 4. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirinoral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167: 117-124.
5. Wahl MJ. Dental surgery in anticoagulated patients. Arch Intern Med. 1998;158:1610-1616. 6. Wahl MJ. Myths of dental surgery in patients receiving anticoagulant therapy. J Am Dent Assoc. 2000;131:77-81. 7. Piersma-Wichers G. [Coagulation disorders: risk factors for bleeding at dental procedures]. Ned Tijdschr Tandheelkd. 1998;105:136-138 [in Dutch]. 8. Kamien M. Remove the tooth, but don’t stop the warfarin. Aust Fam Physician. 2006;35:233-235. 9. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental management considerations for the patient with an acquired coagulopathy, part 1: coagulopathies from systemic disease. Br Dent J. 2003;195:439-445. 10. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental management considerations for the patient with an acquired coagulopathy, part 2: coagulopathies from drugs. Br Dent J. 2003;195:495-501. 11. Alexander R, Ferretti AC, Sorensen JR. Stop the nonsense not the anticoagulants: a matter of life and death. N Y State Dent J. 2002;68:24-26. 12. Brennan MT, Wynn RL, Miller CS. Aspirin and bleeding in dentistry: an update and recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:316-323. 13. Kearon C. Management of anticoagulation in patients who require invasive procedures. Semin Vasc Med. 2003;3:285-294. 14. Dodson TB. Strategies for managing anticoagulated patients requiring dental extractions: an exercise in evidence-based clinical practice. J Mass Dent Soc. 2002;50:44-50. 15. Scully C, Wolff A. Oral surgery in patients on anticoagulant therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:57-64.
ORAL MEDICINE 716 van Diermen, van der Waal and Hoogstraten 16. Gibbons AJ, Sugar AW. Evidence for continuing warfarin during dental extractions. Br Dent J. 2003;194:65. 17. van Diermen DE, Aartman IH, Baart JA, Hoogstraten J, van der Waal I. Dental management of patients using antithrombotic drugs: critical appraisal of existing guidelines. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:616-624. 18. Perry DJ, Noakes TJ, Helliwell PS. Guidelines for the management of patients on oral anticoagulants requiring dental surgery. Br Dent J. 2007;203:389-393. 19. Aframian DJ, Lalla RV, Peterson DE. Management of dental patients taking common hemostasis-altering medications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(suppl): S45.e1-S45.e11. 20. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S-e350S. 21. Gualandro DM, Yu PC, Calderaro D, et al. Guidelines for perioperative evaluation of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2011;96:1-68. 22. Nematullah A, Alabousi A, Blanas N, Douketis JD, Sutherland SE. Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis. J Can Dent Assoc. 2009;75:41. 23. Napenas JJ, Oost FCD, de Groot A, et al. Review of postoperative bleeding risk in dental patients on antiplatelet therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2013;115:491-499. 24. Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. 25. Wray D, Ruiz F, Richey R, Stokes T. Guideline Development Group. Prophylaxis against infective endocarditis for dental proceduresdsummary of the NICE guideline. Br Dent J. 2008;204: 555-557. 26. Richards D. Prophylaxis against infective endocarditis. Evid Based Dent. 2008;9:37-38. 27. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926.
OOOO December 2013 28. Khan KS, Borowiack E, Roos C, et al. Making GRADE accessible: a proposal for graphic display of evidence quality assessments. Evidence Based Medicine. 2011;16:65-69. 29. Boluyt N, Rottier BL, Langendam MW. Guidelines are made more transparent with the GRADE method: considerations for recommendations are explicit in the new method. Ned Tijdschr Geneeskd. 2012;156:A4379. 30. van Diermen DE, Bruers JJ, Hoogstraten J, Bovenlander M, van den Bosch A, van der Waal I. Treating dental patients who use oral antithrombotic medication: a survey of dentists in the Netherlands. J Am Dent Assoc. 2011;142:1376-1382. 31. van Diermen DE, van der Waal I, Hoogvliets MW, Ong FN, Hoogstraten J. Survey response of oral and maxillofacial surgeons on invasive procedures in patients using antithrombotic medication. Int J Oral Maxillofac Surg. 2013;42:502-507. 32. Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxabandan oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108:876-886. 33. Firriolo FJ, Hupp WS. Beyond warfarin: the new generation of oral anticoagulants and their implications for the management of dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:431-441. 34. Little JW. New oral anticoagulants: will they replace warfarin? Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:575-580. 35. Skolarus LE, Morgenstern LB, Froehlich JB, Lisabeth LD, Brown DL. Guideline-discordant periprocedural interruptions in warfarin therapy. Circ Cardiovasc Qual Outcomes. 2011;4: 206-210.
Reprint requests: Denise E. van Diermen, MD, PhD Clinic for Medical-Dental Interaction Academic Centre for Dentistry Amsterdam (ACTA) Gustav Mahlerlaan 3004 1081 LA Amsterdam The Netherlands [email protected]
Management recommendations for invasive dental treatment in patients using oral antithrombotic medication, including novel oral anticoagulants Denise E. van Diermen, MD, PhD,a Isaäc van der Waal, DDS, PhD,b and Johan Hoogstraten, PhDc Academic Centre for Dentistry Amsterdam, Amsterdam, the Netherlands
Objective. The aims were (1) to search the scientific literature from 2007 to 2012 for guidelines and new studies on the dental management of patients using oral antithrombotic medication; (2) to summarize the articles’ evidence and recommendations; and (3) to propose an updated clinical practice guideline for general dentists. Study Design. A systematic literature search in MEDLINE, Embase, and the Guideline websites, from October 2007 to October 2012, produced articles that were critically evaluated. Results. The systematic literature search for guidelines yielded 74 citations (MEDLINE, 45; Embase, 22; and the Guideline websites, 7). Of these, only 2 guideline publications and 2 systematic reviews met the inclusion criteria. They yielded 32 recommendations. Conclusions. The evidence and subsequent recommendations from published guidelines all point in the same direction: do not interrupt oral antithrombotic medication, not even dual antiplatelet therapy, in simple dental procedures. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:709-716)
Oral antithrombotic medication (OAM) has long been used successfully to treat a variety of thrombotic diseases, such as myocardial infarction, stroke, and deep venous thrombosis, and to prevent cardiovascular diseases.1-4 For decades, doctors and patients have worried about the adverse side effects of these medicines, mainly consisting of bleeding complications, either spontaneously or perioperatively. Also in dentistry, this has been a major concern for years, resulting in the advice to temporarily discontinue OAM before invasive dental treatments, such as dental extractions.5-7 Since 1998, several publications have appeared in medical and dental journals5,6,8-12 suggesting that bleeding complications after dental procedures in patients who did not discontinue their antithrombotic medication might not be as serious as previously thought. Furthermore, several studies were published suggesting that the risk of thrombosis after discontinuing OAM might outweigh the bleeding risks while continuing OAM. These considerations have led to several clinical practice guidelines (CPGs) on this topic.13-16 In 2009, a systematic search for guidelines and critical evaluation of these guidelines was performed, a
Assistant Professor and Director of Medicine, Clinic for MedicalDental Interaction, Academic Centre for Dentistry Amsterdam (ACTA). b Professor, Department of Oral and Maxillofacial Surgery/Oral Pathology, Vrije Universiteit Medical Center and Academic Centre for Dentistry Amsterdam (ACTA). c Professor, Department of Social Dentistry and Behavioural Sciences, Academic Centre for Dentistry Amsterdam (ACTA). Received for publication Apr 24, 2013; returned for revision Jul 18, 2013; accepted for publication Jul 23, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.07.026
which led to the conclusion that with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument, only 2 guidelines met the criteria of “good” CPGs.17 One was developed in the United Kingdom18 and one at the International World Workshop of the American Academy of Oral Medicine.19 The aim of this study was to review the dental literature from 2007 to 2012 for additional publications and to propose a CPG for general dentists reflecting the latest evidence as of 2013.
METHODS We used the search strategies from our previous systematic search for guidelines on invasive dental treatment in patients using OAM (as described and published in 200917) to obtain additional guidelines, systematic reviews, and randomized controlled trials (RCTs) published between October 2007 and October 2012 (Tables I and II). We searched MEDLINE, Embase, and the Guideline websites (the National Guideline Clearinghouse [www.guidelines.gov], the Scottish Intercollegiate Guidelines Network [www.sign. ac.uk], the Canadian Medical Association Infobase for Clinical Practice Guidelines [http://www.cma.ca/cpgs/],
Statement of Clinical Relevance General dentists can use the evidence-based recommendations derived from the available evidence described in this article for management of patients using oral antithrombotic medication, including the novel oral anticoagulants. 709
ORAL MEDICINE 710 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table I. MEDLINE search strategy (October 28, 2012) Query No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
Query terms
No. of results
guideline* or practice guideline recommendation* standard* of care practice standard* OR professional standard algorithm OR clinical algorithm* practice algorithm clinical guideline* expert* consensus 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 anticoagulant* aspirin coumadin coumarin* warfarin clopidogrel oral anticoagulant* ticlopidine 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 dentistry dental treatment* dental surgery dental extraction* dental scaling dentoalveolar procedure* dental implant* 19 or 20 or 21 or 22 or 23 or 24 9 and 18 and 25 and 26 limit 27 to human limit 28 to English OR Dutch language limit to date October 2007eOctober 2012
241.975 129.340 244.041 1675 206.863 10.184 5.833 8.286 743.740 193.641 50.447 19.098 14.480 18.744 7.666 4.638 7.293 246.917 411.475 5.540 65.562 1.324 3.906 12 23.947 428.805 158 145 129 45
*The asterisk is a wildcard character.
the Guidelines International Network [www.g-i-n.net], Evidence-Based Medicine Guidelines [www.ebmguidelines.com], the National Institute for Clinical Excellence [www.nice.org.uk]). Inclusion/exclusion criteria Guidelines were included if they were developed for the dental management of patients using antiplatelet or oral anticoagulation medication on the basis of consensus or evidence-based methods. If the guidelines had been updated, the latest version was included. Guidelines based on commentaries and narrative reviews were excluded. Only guidelines written in English or Dutch were reviewed. Systematic reviews and meta-analyses were included if (1) the patients were either on antiplatelet therapy or on vitamin K antagonists (VKAs); (2) the patients had invasive dental procedures performed; (3) the patients were analyzed for bleeding and thrombosis outcomes; and (4) the reviews and metaanalyses included RCTs or cohort studies of sufficient scientific quality. To evaluate the study quality, we used standardized evaluation forms published on the website of the Dutch Cochrane Center (www.dcc.cochrane.org).
RESULTS The systematic literature search for guidelines from October 2007 to October 2012 yielded 74 citations (MEDLINE, 45; Embase, 22; and the Guideline websites, 7) (see Tables I and II). Of these, only 2 guideline publications met the inclusion criteria.20,21 Furthermore, one systematic review and meta-analysis was published in 2009 on dental procedures in patients using warfarin, which reviewed all studies that appeared until June 2008.22 Napenas et al.23 performed a systematic review on dental procedures in patients using single or dual antiplatelet therapy, which included all studies published through September 2011. We collected the levels of evidence (Table III) and levels of recommendations (Table IV) as described and provided by the authors.20,21 In Tables III and IV, we added the results from our former study,17 in which 2 international guidelines were found to be AGREE-able, that is, compatible with the AGREE instrument’s methodologic recommendations.18,19 The recommendations and underlying levels of evidence that were extracted from these guidelines, systematic reviews, and one RCT are summarized in Table V. The gathered recommendations were formulated into a CPG proposal (Table VI). DISCUSSION AND CONCLUSIONS Since the publication in 2007 of 2 evidence-based guidelines in the United Kingdom and the United States,18,19 some additional evidence has emerged from 2 guideline publications, one systematic review on antiplatelet therapy and dental procedures,23 and one meta-analysis on procedures in patients using VKAs.22 Both systematic reviews conclude in concordance with the earlier published guidelines, stating that “continuing the regular dose of warfarin therapy does not seem to confer an increased risk of bleeding when compared with discontinuing or modifying warfarin dose in patients undergoing minor dental procedures”22 and “that there is no indication to alter or discontinue antiplatelet therapy before invasive dental procedures.”23 Several considerations still have to be taken into account. For example, most studies that were included in the systematic reviews were performed in hospital settings and not in outpatient settings. Neither were they performed in patients with comorbid conditions that might influence bleeding after invasive dental procedures. Several medications are known to influence the coagulation system, including nonsteroidal antiinflammatory drugs and drugs that have a potentiating interaction with VKAs, including antifungal agents such as miconazole, which can increase international normalized ratio (INR) values and might enhance
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 711
Table II. Embase search strategy (October 28, 2012) Query No.
Query terms
# 25 #24 AND ([Cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim #24 #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 #23 dental AND implant* AND [2005-2012]/py #22 dentoalveolar AND procedure* AND [2005-2012]/py #21 dental AND scaling AND [2005-2012]/py #20 dental AND extraction* AND [2005-2012]/py #19 dental AND (‘surgery’/exp OR surgery) AND [2005-2012]/py #18 dental AND treatment* AND [2005-2012]/py #17 ‘dentistry’/exp OR dentistry AND [2005-2012]/py #16 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 #15 ‘ticlopidine’/exp OR ticlopidine AND [2005-2012]/py #14 ‘oral’/exp OR oral AND anticoagulant* AND [2005-2012]/py #13 ‘clopidogrel’/exp OR clopidogrel AND [2005-2012]/py #12 ‘warfarin’/exp OR warfarin AND [2005-2012]/py #11 coumarin* AND [2005-2012]/py #10 ‘coumadin’/exp OR coumadin AND [2005-2012]/py #9 ‘aspirin’/exp OR aspirin AND [2005-2012]/py #8 anticoagulant* AND [2005-2012]/py #7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 #6 algorithm OR clinical AND algorithm* AND [2005-2012]/py #5 practice AND standard* OR professional AND (‘standard’/exp OR standard) AND [2005-2012]/py #4 practice AND standard* OR professional AND (‘standard’/exp OR standard) AND [2005-2012]/py #3 standard* AND of AND care AND [2005-2012]/py #2 recommendation* AND [2005-2012]/py #1 guideline* OR practice AND guideline AND [2005-2012]/py
No. of results 44 219,781 41,566 604 1,353 12,210 91,736 76,612 123,752 195,707 5,458 40,826 25,821 29,769 39,104 28,953 65,524 186,803 637,170 39,686 218,811 218,811 412,918 89,971 161,358
*The asterisk is a wildcard character.
bleeding. Furthermore, local factors, such as the degree of inflammation of oral mucosa, might play a role in the risks of developing bleeding after dental surgical procedures. More studies are needed to investigate these additional factors. The preparation of CPGs has received a lot of scientific attention in recent years. Lately, the Board on Health Care Services from the Institute of Medicine in the United States published the latest opinions on good CPG making.24 The common opinion is that guidelines need to be conceived in a formal and transparent way, taking into account factors such as the quality of the guidelines as measured by the AGREE instrument (scope and purpose of the guideline, stakeholder involvement, rigor of development, clarity and presentation, editorial independence). Much attention has been given to the fact that certain evidence can lead to different recommendations, depending on the composition of the guideline committee. One example is the differences in recommendations in the guidelines for the prevention of bacterial endocarditis from the United Kingdom and the United States. In 2008, the UK National Institute for Health and Care Excellence (NICE)25 and the American College of Chest Physicians26 each made a guideline; the American guideline advises to prescribe antibiotics in certain groups of patients undergoing
invasive dental treatments, whereas the UK guideline advises against all antibiotic prophylaxis to prevent bacterial endocarditis in dental patients. Such differences gave rise to the development of the GRADE method (Grading of Recommendations Assessment, Development and Evaluation).27,28 Using the GRADE method can help in gaining insight into the guideline process and into the way recommendations are derived from evidence or even lack of evidence. In the present article, we have summarized only the recommendations based on evidence and used these to formulate a proposal for a CPG. In a definitive CPG, the independence of the guideline makers should be clearly stated, and GRADE should be used to clarify how evidence led to the recommendations. GRADE is one method that tries to tackle this problem and helps guideline makers to get insight into the underlying considerations and make them more explicit when making recommendations, by including the quality of the evidence and the strength of the recommendations. This method has been adopted by well-established guideline-making institutions, such as NICE, the World Health Organization, the Cochrane Collaboration, and the Dutch Institute for Healthcare Improvement (CBO) in the Netherlands.29 Another important issue is the opinion of the patients. The patients’ views
ORAL MEDICINE 712 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table III. Definition of the levels of evidence as described by other clinical practice guidelines Levels of evidence used by Aframian et al.19: Level A: Based on multiple randomized controlled trials Level B: Based on data from a single randomized trial or nonrandomized studies Level C: Expert opinion Classification of evidence levels used by Perry et al.18: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasiexperimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies, and case studies IV Evidence obtained from expert committee reports or opinions or from clinical experiences of respected authorities Levels of evidence of the Brazilian Society of Cardiology21 A. Evidence in several populations from multiple randomized clinical trials or meta-analyses B. Evidence in a limited group of populations from a single randomized clinical trial or from nonrandomized clinical studies C. Evidence in a very limited group of populations from consensus and experts’ opinions, case reports, and series Classification of evidence levels used by Douketis et al.20 Grade of recommendation
Benefit vs risk and burden
Methodologic strength of the supporting evidence
Strong recommendation, highquality evidence (1A)
Benefits clearly outweigh risk and burdens or vice versa.
Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies.
Strong recommendation, moderate-quality evidence (1B)
Benefits clearly outweigh risk and burdens or vice versa.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies.
Strong recommendation, low- or very-low-quality evidence (1C)
Benefits clearly outweigh risk and burdens or vice versa.
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Weak recommendation, highquality evidence (2A)
Benefits closely balanced with risks and burdens.
Consistent evidence from randomized controlled trials without important limitations or exceptionally strong evidence from observational studies.
Weak recommendation, moderatequality evidence (2B)
Benefits closely balanced with risks and burdens.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or very strong evidence from observational studies.
Weak recommendation, low- or very-low-quality evidence (2C)
Uncertainty in the estimates of benefits, risks, and burdens; benefits, risk, and burdens may be closely balanced
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Implications Recommendation can apply to most patients in most circumstances. Further research is very unlikely to change our confidence in the estimate of effect. Recommendation can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate. Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate. The best action may differ depending on circumstances or patient or societal values. Further research is very unlikely to change our confidence in the estimate of effect. Best action may differ depending on circumstances or patient or societal values. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate. Other alternatives may be equally reasonable. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate.
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 713
Table IV. Definition of the grades of recommendations Classes of recommendations used by Aframian et al.19: Class I: Benefit to patients clearly outweighs any risks; procedure SHOULD be performed Class II: Conflicting evidence or a divergence of opinion about the usefulness of a procedure or treatment IIa: Benefit seems to outweigh the risk; weight of evidence is in favor of usefulness. IT IS REASONABLE to perform the procedure IIb: Benefit seems to outweigh the risk; usefulness is less well established. IT IS NOT UNREASONABLE to perform the procedure Class III: Risk outweighs the benefit; IT MAY BE HARMFUL AND IS UNHELPFUL. Procedure should NOT be performed Classification of grades of recommendations used by Perry et al.18: A. Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendation. (Evidence levels Ia, Ib) B. Requires the availability of well conducted clinical studies but no randomized clinical trials on the topic of recommendation. (Evidence levels IIa, IIb, III) C. Requires evidence obtained from expert committee reports or opinions or from clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV) Classification of degree of recommendations used by Brazilian Society of Cardiology21: Degree of Recommendation IdBenefit >>> Risk; the treatment/procedure must be indicated/administered; Degree of Recommendation IIadBenefit >> Risk; the choice for the treatment/procedure may help the patient; Degree of Recommendation IIbdBenefit > Risk; it is not defined if the treatment/procedure can help the patient; Degree of Recommendation IIIdRisk > Benefit; the treatment/procedure must not be performed because it does not help and may be harmful for the patient. Classification of grades of recommendation used by Douketis et al.20: 1A. Strong recommendation, high-quality evidence 1B. Strong recommendation, moderate-quality evidence 1C. Strong recommendation, low- or very-low-quality evidence 2A. Weak recommendation, high-quality evidence 2B. Weak recommendation, moderate-quality evidence 2C. Weak recommendation, low- or very-low-quality evidence
should be incorporated into the CPG-making process, because their perspectives warrant representation in the CPG. Two surveys relevant to the present study have been undertaken in the Netherlands, one among general dentists30 and one among oral and maxillofacial surgeons (OMSs)31; both found that dentists and OMSs have very variable management strategies in patients using antiplatelet medicines, such as aspirin, as well as in patients using VKAs, such as acenocoumarol. Both dentists and OMSs did express the need for a Dutch CPG on this topic. The accumulated evidence and recommendations from this study can be helpful to compose such a guideline. Unfortunately, international guidelines cannot be accepted unchanged, but have to be adapted to local circumstances and the needs of patients, dentists, and medical specialists. In the final version of a CPG, clinical questions for which no clinical studies have been undertaken are relevant. For example: Is it safe to treat patients with oral anticoagulation with dental implants, which dental procedures are considered more invasive, and what should be the management? How should dentists treat patients using the new generation of oral antithrombotic medicines, the novel oral anticoagulants (NOACs), such as rivaroxaban (Xarelto; Bayer Healthcare AG, Leverkusen, Germany) and dabigatran (Pradaxa; Boehringer Ingelheim, Ridgefield, CT)?
Turpie et al.32 advise not to interrupt rivaroxaban in procedures with a low risk of bleeding, such as simple tooth extraction. They also advise to avoid interventions at peak rivaroxaban activity, that is, 2 to 4 hours after dosing. Although there is no antidote to the NOACs, these medications have a short half-life of 5 to 9 hours, and their anticoagulating effect will wear off much sooner than that of VKAs, although the effect can last longer in elderly patients.32 In this journal, 2 comprehensive articles by Firriolo et al.33 and Little34 were published in 2012 about the NOACs and the suggested recommendations for dental procedures. Furthermore, the problem of implementing evidence and evidence-based CPGs into practice remains a problem. Several studies have found that since 2007, general dentists and OMSs throughout the Western world still advise patients to interrupt their OAM for simple dental treatments, exposing these patients to increased thrombotic risks.35 In this article we presented the scientific evidence and subsequent recommendations from the medical and dental literature until October 2012 that can be used as a sound base for an up-to-date CPG on the management of dental patients using OAMs and undergoing simple dental procedures. We excluded recommendations without scientifically evident sources and produced a management advice sheet for general dentists (see Table VI).
ORAL MEDICINE 714 van Diermen, van der Waal and Hoogstraten
OOOO December 2013
Table V. Review of the recommendations from guidelines and systematic reviews on patients undergoing dental surgery using oral antithrombotic drugs (aspirin, clopidogrel, warfarin, and novel oral anticoagulants, such as dabigatran and rivaroxaban) Level of evidence* 1. Continuation of antithrombotic drugs a. Antiplatelet medications Do not interrupt low-dose aspirin therapy (100 mg or less) for outpatient dental procedures.19,21 Continue ASA around the time of minor dental procedures in patients who are receiving ASA for the secondary prevention of cardiovascular disease.20 Do not alter or stop single or dual antiplatelet therapy for invasive dental treatment (single or multiple tooth extractions, deep scaling and probing, biopsies, flap surgery, gingivectomy, alveoloplasty).19 b. Oral anticoagulants (warfarin) Oral anticoagulants should not be discontinued in the majority of patients requiring outpatient dental surgery, including extraction.18 When the INR is less than 3.5, do not modify or discontinue warfarin therapy for simple single dental extractions.19 When the INR is 3.5 or more and complicated or invasive oral surgery procedures are planned, discuss with physician.19 Continue VKAs with an oral prohemostatic agent in patients who require a minor dental procedure.20 Do not discontinue OAM before simple surgeries (e.g., extraction of 3 teeth, gingival surgery, periodontal scaling) in patients with INR < 3.0.21 Do not discontinue or modify the regular dose of warfarin for patients undergoing minor dental procedures (up to 5 dental extractions or 6 dental implants).21 c. Low-molecular-weight heparin Consult physician of patient on low-molecular-weight heparin for advice on continuing, altering, or stopping of medication before dental procedure.19 2. Antibiotics No need to change anticoagulation regimen when a single dose of prophylactic antibiotic is used.18,21 3. Preoperative measures Check INR 72 hours before dental surgery in patients that have stablez INRs.18 Check INR at least 24 hours before the dental procedure.21 Evaluation of INR 72 hours before the procedure is acceptable in stablez patients.21 Discuss with physician in charge when INR 3.0 and the planned procedures are more extensive.21 Assess the patient’s complete medical history.21 Schedule a larger number of visits when there is extraction of more than 3 teeth.21 Plan the surgeries earlier in the day and in the beginning of the week.21 4. Operative measures Inform the patients that minor bleeding or oozing from gingival mucosa may be more common when not interrupting VKAs during dental procedures.20 Minimize surgical trauma.21 Reduce areas of periodontal surgery and scaling and root planing (per quadrant).21 5. Postoperative pain control Do not prescribe NSAIDs and COX-2 inhibitors as analgesics.18 Consider using gelatin sponges, fibrin glue, fibrin adhesive dressing, oxidized cellulose, or 3-aminocaproic acid mouthwash.19 Give patients on OAC a 2-day regimen of postoperative 4.8% tranexamic acid mouthwash.19 Give patients who do not interrupt VKAs a 5-mL oral dose of tranexamic acid, 5 to 10 min before the dental procedure and 3 to 4 times daily for 1 to 2 days after the procedure.20 Remove nonabsorbable sutures after 4 to 7 days.21 Compress with gauze for 15 to 30 minutes after the surgical procedure.20 Use coagulating agents, such as gelatin sponges, oxidized regenerated cellulose, synthetic collagen, or tranexamic acid mouthwash in 4.8% aqueous solution during and 7 days after the surgery, using 10 mL, 4 times a day for 2 minutes.21 6. Referral Refer patients whose INR is unstable.z,18
Recommendation class, grade, or degreey
Level B
Class I Grade 2C
Level 1A
Class I
Level Ib
Grade A
Level A
Class I
Level A
Class I Grade 2C
Level C Level 1A
Class I
Level C
Level IV18/ Level C21
Grade C18/ Degree I21
Level Level Level Level Level Level Level
Grade A Degree I Degree I Degree I Degree I Degree I Degree I
Ib IC C C C C C
Grade 2C Level C Level C
Degree I Degree I
Level III Level B
Grade B Class I
Level A
Class I Grade 2C
Level C Level C Level C
Degree I Degree I Degree I
Level Ib
Grade A
OAC, oral anticoagulation; OAM, oral antithrombotic medication; TAR, thrombocyte aggregation inhibitor; ASA, acetylsalicylic acid; VKA, vitamin K antagonist; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase-2. *Levels of evidence are explained in Table III. y Degrees of recommendation are explained in Table IV. z No definition of stable and unstable INRs was given in the cited articles.
OOOO Volume 116, Number 6
ORIGINAL ARTICLE van Diermen, van der Waal and Hoogstraten 715
Table VI. Proposal for a 2013 clinical practice guideline for general dental practitioners Recommendations to general dental practitioners when planning invasive dental treatment for patients using oral antithrombotic medication and undergoing simple dental treatment (e.g., single or multiple dental extractions up to 3 teeth, up to 3 dental implants, scaling and root planing, probing, flap surgery, apex resection, alveoloplasty): 1. Continuation of OAM a. Do not interrupt single or dual TAR (such as ASA, clopidogrel, and carbasalate calcium). b. Do not interrupt VKAs if the INR is less than 3.5. c. Do not interrupt NOACs (direct thrombin inhibitors or Xa-inhibitors, such as apixaban, dabigatran, and rivaroxaban). Note: The anticoagulation regime does not require alteration when single-dose antibiotics for prophylaxis are provided; miconazole is contraindicated when VKAs or NOACs are taken. 2. Preoperative measures: a. Inform the patients that minor bleeding or oozing from gingival mucosa may be more common when not interrupting OAM during dental procedures. b. Check INR in patients using VKA at least 24 to 72 hours before the dental procedure; refer patients whose INR is higher than 3.5 to the hospital for evaluation and treatment. c. Advise patients on NOACs not to take medication 1 to 3 hours immediately before dental treatment. d. Assess the patients’ complete medical history and discuss with the physician in charge if renal or liver disorders are suspected or known; when INR 3.5 or the planned procedures are more extensive. e. Schedule extraction of more than 3 teeth over a larger number of visits (i.e., divide the load) and plan the surgeries earlier in the day and at the beginning of the week. 3. Perioperative measures: a. Minimize surgical trauma and reduce areas of periodontal surgery and scaling and root planing (per quadrant). b. Aim at primary closure of surgical wounds, including extraction wounds, using absorbable sutures. 4. Postoperative measures: a. Compress with gauze for 15 to 30 minutes after the surgical procedure; use coagulating agents, such as gelatin sponges, oxidized regenerated cellulose, synthetic collagen, or tranexamic acid mouthwash in 4.8% aqueous solution, during 1 to 2 days after the surgery, using 10 mL, 4 times a day for 2 minutes. b. Remove nonabsorbable sutures, if used, after 4 to 7 days. c. Do not prescribe NSAIDs and COX-2 inhibitors as analgesics to any patient on any antithrombotic medications. d. Provide the patients with oral and written instructions about the expected postoperative course and the measures they can take if bleeding occurs. OAM, oral antithrombotic medication; TAR, thrombocyte aggregation inhibitor; ASA, acetylsalicylic acid; VKA, vitamin K antagonist; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase-2.
The evidence and subsequent recommendations all point in the same direction: do not interrupt OAM, not even dual antiplatelet therapy, in simple dental procedures. With certain precautions, this seems to be a safe way to treat dental patients in need of minor invasive dental treatments while continuing their OAM.
REFERENCES 1. Seshasai SRK, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172:209216. 2. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;42: 227-276. 3. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative metaanalysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. 4. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirinoral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167: 117-124.
5. Wahl MJ. Dental surgery in anticoagulated patients. Arch Intern Med. 1998;158:1610-1616. 6. Wahl MJ. Myths of dental surgery in patients receiving anticoagulant therapy. J Am Dent Assoc. 2000;131:77-81. 7. Piersma-Wichers G. [Coagulation disorders: risk factors for bleeding at dental procedures]. Ned Tijdschr Tandheelkd. 1998;105:136-138 [in Dutch]. 8. Kamien M. Remove the tooth, but don’t stop the warfarin. Aust Fam Physician. 2006;35:233-235. 9. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental management considerations for the patient with an acquired coagulopathy, part 1: coagulopathies from systemic disease. Br Dent J. 2003;195:439-445. 10. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental management considerations for the patient with an acquired coagulopathy, part 2: coagulopathies from drugs. Br Dent J. 2003;195:495-501. 11. Alexander R, Ferretti AC, Sorensen JR. Stop the nonsense not the anticoagulants: a matter of life and death. N Y State Dent J. 2002;68:24-26. 12. Brennan MT, Wynn RL, Miller CS. Aspirin and bleeding in dentistry: an update and recommendations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:316-323. 13. Kearon C. Management of anticoagulation in patients who require invasive procedures. Semin Vasc Med. 2003;3:285-294. 14. Dodson TB. Strategies for managing anticoagulated patients requiring dental extractions: an exercise in evidence-based clinical practice. J Mass Dent Soc. 2002;50:44-50. 15. Scully C, Wolff A. Oral surgery in patients on anticoagulant therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:57-64.
ORAL MEDICINE 716 van Diermen, van der Waal and Hoogstraten 16. Gibbons AJ, Sugar AW. Evidence for continuing warfarin during dental extractions. Br Dent J. 2003;194:65. 17. van Diermen DE, Aartman IH, Baart JA, Hoogstraten J, van der Waal I. Dental management of patients using antithrombotic drugs: critical appraisal of existing guidelines. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:616-624. 18. Perry DJ, Noakes TJ, Helliwell PS. Guidelines for the management of patients on oral anticoagulants requiring dental surgery. Br Dent J. 2007;203:389-393. 19. Aframian DJ, Lalla RV, Peterson DE. Management of dental patients taking common hemostasis-altering medications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(suppl): S45.e1-S45.e11. 20. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S-e350S. 21. Gualandro DM, Yu PC, Calderaro D, et al. Guidelines for perioperative evaluation of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2011;96:1-68. 22. Nematullah A, Alabousi A, Blanas N, Douketis JD, Sutherland SE. Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review and meta-analysis. J Can Dent Assoc. 2009;75:41. 23. Napenas JJ, Oost FCD, de Groot A, et al. Review of postoperative bleeding risk in dental patients on antiplatelet therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2013;115:491-499. 24. Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. 25. Wray D, Ruiz F, Richey R, Stokes T. Guideline Development Group. Prophylaxis against infective endocarditis for dental proceduresdsummary of the NICE guideline. Br Dent J. 2008;204: 555-557. 26. Richards D. Prophylaxis against infective endocarditis. Evid Based Dent. 2008;9:37-38. 27. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926.
OOOO December 2013 28. Khan KS, Borowiack E, Roos C, et al. Making GRADE accessible: a proposal for graphic display of evidence quality assessments. Evidence Based Medicine. 2011;16:65-69. 29. Boluyt N, Rottier BL, Langendam MW. Guidelines are made more transparent with the GRADE method: considerations for recommendations are explicit in the new method. Ned Tijdschr Geneeskd. 2012;156:A4379. 30. van Diermen DE, Bruers JJ, Hoogstraten J, Bovenlander M, van den Bosch A, van der Waal I. Treating dental patients who use oral antithrombotic medication: a survey of dentists in the Netherlands. J Am Dent Assoc. 2011;142:1376-1382. 31. van Diermen DE, van der Waal I, Hoogvliets MW, Ong FN, Hoogstraten J. Survey response of oral and maxillofacial surgeons on invasive procedures in patients using antithrombotic medication. Int J Oral Maxillofac Surg. 2013;42:502-507. 32. Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxabandan oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108:876-886. 33. Firriolo FJ, Hupp WS. Beyond warfarin: the new generation of oral anticoagulants and their implications for the management of dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:431-441. 34. Little JW. New oral anticoagulants: will they replace warfarin? Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:575-580. 35. Skolarus LE, Morgenstern LB, Froehlich JB, Lisabeth LD, Brown DL. Guideline-discordant periprocedural interruptions in warfarin therapy. Circ Cardiovasc Qual Outcomes. 2011;4: 206-210.
Reprint requests: Denise E. van Diermen, MD, PhD Clinic for Medical-Dental Interaction Academic Centre for Dentistry Amsterdam (ACTA) Gustav Mahlerlaan 3004 1081 LA Amsterdam The Netherlands [email protected]